Bicyclononane diol and esters

ABSTRACT

WHEREIN Z1 and Z2 represent independent free or esterified hydroxy groups are produced by reducing 2,5,11trioxatricyclo(4,3,1,14,8)undecan-3-one; they are intermediates for the synthesis of prostaglandins. Compounds of formula

United States Patent i191 Woodward Aug. 26, 1975 BICYCLONONANE DIOL ANDESTERS [75] Inventor: Robert Burns Woodward,

Cambridge, Mass.

[73] Assignee: Ciba-Geigy Corporation, Ardsley,

[22] Filed: Feb. 2, 1973 [21] Appl. No.: 329,252

OTHER PUBLlCATlONS Andre Pernot et al., Bull. soc. chim. France, (1953),pp. 321-323. Fieser 84 Fieser, Reagents for Organic Synthesis,

(1967), pp. 1049-1053, ll80-H8l.

Wagner and Zook, Synthetic Organic Chemistry, 1953). p- 823.

Primary ExaminerNorma S. Milestone Attorney, Agent, or Firm-Joseph G.Kolodny; John .I. Maitner; Theodore O. Groeger ABSTRACT Compounds offormula wherein Z and 2; represent independent free or esterifiedhydroxy groups are produced by reducing 2,5,1 ltrioxatricyclo[4,3,l,l"}undecan-3-one', they are intermediates for the synthesis ofprostaglandins.

6 Claims, No Drawings BICYCLONONANE DIOL AND ESTERS The presentinvention relates to a new dioxabicyclononane diol, the esters thereof,and to a process for the manufacture of these compounds. The newcompounds are valuable intermediate products for the manufacture ofbiologically highly potent prostaglandins by a new, stericallycontrolled method process.

The invention relates in particular to new 2,4-dioxabicyclo[3,3,l]nonanes of the formula II 1 2 v w z (I1).

known, naturally occurring prostaglandins as well as of new syntheticprostaglandins. The individual steps proceed with high yields. The newintermediate products are therefore suitable for carrying out thesynthesis of the cited prostaglandins on an industrial scale.

From these intermediate products it is possible to manufacture first andforemost the prostaglandins of the F -series which are characterised byan optionally unsaturated a-alkanecarboxylic acid in 8-position, ana-hydroxyolefine grouping in l2-p0sition and two a-hydroxy groups in 9,]l-position. Secondly, it is possible to use the new compounds asintermediate products for the manufacture of prostaglandins of the E, Aand B series, and furthermore of derivatives and homologs ofprostaglandins.

The biological activity and the importance of prostaglandins in medicineare known and described, for example, by M. P. L. Caton in Progr. Med.Chem. 8, 3l7 l97l The standard prostaglandin numbering used herein isderived from prostanoic acid which has the following structure:

In the above formulae, as well as in those hereinafter, dotted linesindicate substituents which are situated behind the plane defined by thecyclopentane ring; these substituents are denoted by a. Thickly drawnlines indicate substituents which are in front of this plane; these aredenoted by B. Substituents linked by wavy lines can be in the aorB-configuration. The standard prostaglandin nomenclature is used asillustrated hereinabove in the formula of prostanoic acid. For thestandard prostaglandin nomenclature compare also S. Bergstrom, Science,157, 382 (I967), M. P. L. Caton, Progr. Med. Chem. 8, 317, I971 andNiels Andersen, Annals of the New York Academy of Sciences, Vol. 180, S.14, April 30, l97l.

The stereospecific manufacture of the cited prostaglandins using the newcompounds according to the invention is carried out by a new andoriginal multi-step process. The following scheme reproduces, forexample, the synthesis of natural prostaglandins F (FGF (Xllla) and F(F'GF (XIIIB).

z cil H H 9. a. 7. 9 o o H o l l l (Xmbml (Xlu,b) (Xllu ,b) (Xlllmb) Inthe formulae Xa, Xla, Xlla and Xllla, R represents the group in theformulae Xb, Xlb, XIlb and Xlllb, R represents the group H H H l l CC-CCH C CCH .CH,-,

| *4 H H OH and in the formula Xe, R represents the group In the abovescheme, only those compounds which lead to the naturally occurringprostaglandins F and F have been specified. The optical antipodes anddiasteroisomers which occur in the reactions, and their separation, willbe dealt with in what follows hereinafter.

The individual reaction steps are described briefly below, but nolimitation to these reaction conditions and to the specifically citedreagents is to be deduced therefrom.

1st. Step Cis-cyclohexane-l,3,5-triol [K. H. Steinaeker and H. Stetter,Chem. Ber. 85, 451 (I952)] is converted with glyoxylic acid, or areactive functional derivative thereof, e.g. its hydrate, an ester or anaeetal, into the compound of the formula I, in which X, and X togetherrepresent the oxo group. The reaction is advantageously carried out inthe presence of an acid catalyst, e.g. p-toluenesulphonic acid, in aninert solvent, e.g. benzene or ethylene glycol dimethyl ether, at atemperature of about 20C to the boiling point of the solvent employed.

The compound of the formula I, in which X, represents a hydrogen atomand X represents the hydroxy group, is formed when eis-cyclohexanel,3,5-triol is reacted under similar conditions with glyoxal, or areactive functional derivative thereof, e.g. the hydrate or one of itsacetals.

2nd. Step A compound of the formula I is converted by reduction into acompound of the formula II, wherein Z, and Z are hydroxy groups. Complexhydrides, e.g. lithium aluminium hydride, lithium borohydride or sodiumborohydride, can be used as reducing agents. The reduction is carriedout at reduced or slightly elevated temperature, preferably betweenabout lOC and lOOC, in a suitable solvent. Lithium aluminium hydride orlithium borohydride are preferably used in ethereal liquids, such asdiethyl ether, ethylene glycol dimethyl ether, diethylene glycoldimethyl ether, tetrahydrofuran or dioxan. It is also possible to carryout the reduction with sodium borohydride in lower alkanols, such asmethanol, ethanol, isopropanol or tert. butanol, or also in water.

3rd. Step The compound falling under the formula II manufactured in the2nd. step, in which Z, and Z are hydroxy groups, is converted withmethanesulphonyl chloride and pyridine into its dimesylate, which alsofalls under the formula II. The reaction can be carried out in pyridineas solvent and maintaining low temperatures, about 20C. According toanother esterifieation method, it is possible to use triethylamine asprotonaeeeptor and methylene chloride as solvent.

4th. Step The compound of the formula II, wherein Z, and Z representesterified hydroxy groups, e.g. mesyloxy groups, is converted into thecompound of the formula III, in which Z, has the same meaning as in thestarting material, by splitting off HZ with a base to form the doublebond. Organic or inorganic bases can be used as bases. Particularlysuitable bases are 1,5- diazabicyelo [5,4,0]undec-S-ene, which can beused in e.g. dimethyl sulphoxide at a temperature of about l 10C, ortetra-n-butylammonium fluoride, which can The bieyclic compound of theformula III, wherein Z, is for example a mesyloxy group, or thecorresponding racemate, can be converted in surprising manner into thetricyclic compound of the formula IV, wherein Z is a hydroxy group. Thisreaction is surprising because normally the formation of twosix-membered rings, but not of a five-membered and a seven-memberedring, would be expected.

The reaction is preferably carried out in a watermiscible solvent, e.g.in ethylene glycol dimethyl ether/water mixture, in the presence ofpotassium carbonate at a temperature of about 80C.

The reactions of the 4th. and 5th. steps can also be carried out in oneoperation by treating a diester falling under the formula II, e.g.dimesylate, with a solution of hydroxyl ions, e.g. with an alkalisolution, such as a potassium hydroxide solution in a solvent, such asin a lower alkanol, e.g. isopropanol. If desired, the crude compound ofthe formula IV, or its racemate, can be purified via its acetate.

Ifa start is made from the racemit mixture, consisting of the compoundof the formula III and its optical antipode, there is obtained theracemit mixture consisting of the compound of the formula IV and itsoptical antipodes. The separation into the antipodes can also beeffected in this step as described further on. However, instead ofstarting from the racemate, it is also possible to start from theoptically active compound of the formula III, in the process of whichthe optically active compound of the formula IV is obtained directly.

6th. Step The secondary alcohol of the formula IV, wherein Z:, is ahydroxy group, or its racemate, is converted in the usual manner withmethanesulphonyl chloride and a suitable base, e.g. triethylamine orpyridine, in a suitable solvent, e.g. in methylene chloride, into thecompound of the formula IV, in which 2,, represents the mesyloxy group.If desired, it is also possible in this step to effect the resolutioninto the optical antipodes, as described later in more detail.

5 7th. Step The methylsulphonyl ester of the formula IV, or itsracemate, is converted into the unsaturated compound of the formula V,or its racemate, by splitting off methanesulphonic acid. The splittingoff is effected in the presence of a base, e.g. potassium tert.butylate, or 1,5- diazabicyclo [5,4,0]undec-5-ene, in a solvent, e.g.dimethyl sulphoxide, or, preferably, in the presence of an alkalihydroxide, such as potassium hydroxide, in a boiling lower alkanol, suchas isopropanol.

8th. Step The unsaturated compound of the formula V, or its racemate, isoxidised with e.g. a hydroperoxide, for example, a peracid, such asm-chloroperbenzoic acid, or, preferably, with a peroxyimidic acid, forexample peroxybenzimidic acid, to a mixture consisting of the a-epoxideof the formula VI and the corresponding B-epoxide, or the racematesthereof, preferably at slightly elevated temperature or elevatedtemperature, e.g. between about C and 50C. When using a peracid, such asm-chloroperbenzoic acid, the B epoxide is formed as main product; whenusing a peroxyimidic acid, such as peroxybenzimidic acid, which can bepre pared from an optionally substituted benzonitrile or lower alkylnitrile with hydrogen peroxide in the presence of a base, such as analkali metal bicarbonate, e,g. potassium bicarbonate, in a solvent, suchas a lower alkanol, e.g. in methanol, surprisingly more 11- thanB-epoxide is obtained. Both epoxides can be separated, for example, bychromatography, or further processed as a mixture. The separatedB-epoxide, or its racemate, can be reduced with a complex hydride, e.g.with lithium aluminium hydride, in a solvent, e.g. in tetrahydrofuran,to an alcohol of the formula IV, or its racemate. The B-epoxide isthereby led back into the process. In this step it is also possible toperform any desired racemate separation.

9th. Step In an a-epoxide of the formula VI, or its racemate, it ispossible to open the epoxide ring, for example, with ammonia in asolvent, such as water, at elevated temperature, e.g. between about 50Cand 150C, optionally under pressure, in the process of which a compoundof the formula VII, its racemate or acid addition salts thereof, areformed. The epoxide ring is opened in such a way that the4B-amino-Sa-hydroxy compound of the formula VII, or its racemate, isformed. The pos sible isomeric 5B-amino-4a-hydroxy compound is notobtained, or is obtained in undetectably small amounts. If desired, itis possible to resolve an optionally resulting racemate.

th. Step A compound of the formula VII, its racemate or an acid additionsalt thereof, can be converted in the presence ofa lower alkanol, suchas methanol, by treatment with an acid, for example a hydrohalic acid,e.g. hydro chloric acid, into a compound of the formula VIII, wherein Zrepresents lower alkoxy, e.g. methoxy, its racemate or an acid additionsalt thereof. The reaction can be carried out at slightly reduced orelevated temperature, eg between about 0 and 50C. It is also possiblehere to resolve an optionally resulting racemate.

Steps 8-10, ie the epoxidation of an olefine, amininolysis of theepoxide and splitting of the 6-10 bond in the tricyclic skeleton, canalso be carried out in another sequence. For example, in an a-epoxide ofthe formula VI, or its racemate, the 6-10 bond can be split according tothe reaction conditions of the 10th. step, and in the resulting2,3-endo-epoxy-4-endo-hydroxy-8- alkoxy-7-oxabicyclo[4,3,0]nonane of theformula VI, or in the racemate thereof, the epoxy grouping can beaminolysed according to the method of the 9th. step, in the process ofwhich a compound of the formula VIII, or its racemate, is formed,Furthermore, in a tricyclic olefine of the formula V, or in itsracemate, it is possible to cleave the 6l0 bond according to thereaction conditions of the 10th. step and, in the resulting bicyclicolefine of the formula V, or in its racemate, to epoxidise the doublebond according to the method of the 8th. step, whereupon once again acompound of the formula VI, or its racemate, is obtained.

1 1th. Step From the compound of the formula VIII, its racemate or anacid addition salt thereof, it is possible to split off the amino group,in the process of which a ring contraction simultaneously takes placeand an aldehyde of the formula IX, wherein Z is lower alkoxy, such asmethoxy, and Z is hydroxy, or its racemate, is formed. The splitting offcan be performed by diazotisation, e.g. with nitrous acid, prepared insitu from one of its salts, such as sodium nitrite, and an acid, such asacetic acid, or with an anhydride of nitrous acid, such as dinitrogentetroxide, in a solvent, such as water, or in an ethereal solvent, suchas ethylene glycol monomethyl ether, preferably at reduced temperature,e.g. between about 10 and +50C. If desired, it is also possible toresolve an optionally obtained racemate by one of the methods describedlater herein, into both its optical antipodes.

12th. Step The aldehyde of the formula IX, wherein Z, represents methoxyand Z represents hydroxy, or its nice mate, can be used for thesynthesis of primary steps which lead either to prostaglandin F or alsoto F The compound of the formula Xa can be manufactured therefrom byreaction with the Wittig reagent which is prepared in the conventionalmanner from 2- (S)-hydroxy-n-heptyltriphenylphosphonium iodide andmethyl lithium IE. .1. Corey et al., Ann. New York Acad. Sci. 33(1971)]. The reaction takes place at temperatures between about 78C andabout 25C in tetrahydrofuran or ethylene glycol dimethyl ether, in theprocess of which a transdouble bond is formed. The compound of theformula Xb can be manufactured therefrom in analogous manner by usingthe known Wittig reagent fromcis-2-(S)-hydroxy-4-n-heptenyltriphenylphosphonium iodide (E. 1. Coreyet al., J. Am. Chem. Soc. 93, 1490 (1971)].

If the racemate consisting of the compound of the formula VI and itsoptical antipodes is used as starting material, there is obtained andiastcreoisomer mixture which, with the aid of physicochemicalseparating op erations, can be separated or further processed as such.

If instead of 2(S)-hydroxy-n-heptyl-triphenylphosphonium iodide there isused racemic Z-hydroxy-nheptyl-triphenylphosphonium iodide or thecorresponding heptenyl derivatives, once again a diastereoisomer mixtureis obtained which likewise can either be further processed or separatedby the aid of physicochemical separating operations. The samediastereoisomer mixture is obtained by using instead of the 2-hydroxy-heptyl or 2-hydroxy-heptenylphosphonium compounds acorresponding 2-oxo-heptylor 2-oxoheptenyl derivative, e.g.I-triphenylphosphonium-2- heptanone-bromide or thel-triphenylphosphoranylidene-Z-heptanone prepared therefrom with sodiumhydrogen carbonate [M. Miyano and C. R. Dorn, Tetrahedron Letters l6l51969)], and reducing the resulting ketones of the formula Xc with acomplex hydride, such as sodium borohydride. The two racemates obtainedthereby can again either be further processed as such or resolved intotheir respective two optical antipodes with optically active auxiliaryproducts by methods later described herein.

13th. Step The cyclic acetals of the formulae Xa and Xb, wherein Z,represents e.g. methoxy and 2 represents hydroxy, their racemates or thecorresponding diastereoisomer mixtures, are hydrolysed under acidconditions to the compound of the formula Xla or Xlb or to thierracemates.

These compounds can be in the form of the free aldehyde or in that ofthe cyclic hemiacetal of the formula XII. in using optically activestarting material of the formula Xa or Xb, the trihydroxy compoundsalready contain all steric prerequisites for their conversion in thenext step into the natural, optically active F'GF a and PGE, [f a startis made from the racemate of a compound of the formula Xa or Xb, theracemate is ob- ;ained which consists of a mixture of the compound of:he formula Xla or Xlb and the optical antipodes :hereof. The separationof the racemate can be effected )y one of the conventional processeslater described 'lerein. By starting from the diastereoisomer mixtureswhich may be obtained in the l2th. step, once again iiasteroisomermixtures are obtained which can be furvher processed as such or resolvedanalogous to the nethods mentioned in the 12th. step.

14th. Step The compounds of the formula Xla or Xlb, corre- .pondinghemiacetals of the formula Xlla or Xllb or llSO the correspondingracemates or diastereoisomer nixtures, are finally converted with theWittig reagent 'rom -triphenylphosphonovaleric acid {5. 1. Corey, T.Schaaf, W. Huber, U. Koelliker and N. M. Weinhenker, J. Amer. Chem. Soc.92, 397 (1970) and l,5675 (l969)] in dimethyl sulphoxide [R. Greenvald,M. Chaykowsky and E. .1. Corey, J. Org. Chem. [8, H28 (l963)] into theprostaglandin F of the 'ormula Xllla or F of the formula Xlllb,Preferably l cis-double bond is formed in this reaction.

The natural, optically active PGF a or F is obained directly by usingoptically active starting mateial of the formulae Xla or Xlb, Xlla orXllb. By startng from the racemate of the compound of the formula (Ia orXlb or Xlla or Xllb, a racemate is obtained vhich consists of a mixtureof natural PGF a and G1 a and the optical antipodes thereof. Theracenate separation can be effected by one of the convenional methodslater described herein.

If a start is made from the diastereoisomer mixtures vhich may beobtained in the 13th. step, once again nixtu res are obtained whichconsist of the naturally ocurring prostaglandin F and F and theirdiasteroisomers, which can be used as such or resolved as nentioned inthe 12th. step.

The racemates mentioned hereinbefore can be reolved into their opticalantipodes by methods which re known per se.

One of these methods consists in reacting a racemate rith an opticallyactive auxiliary substance, separating the resulting mixture of twodiastereoisomer compounds with the aid of appropriate physicochemicalmethods and then resolving the individual diastereoisomeric compoundsinto the optically active starting materials.

Particularly suitable racemates for resolution into the antipodes arethose which possess an acid group, e.g. the racemate of the compound ofthe formula Xlll. It is possible to convert other described racematesinto acid racemates by simple reactions. For example, the aldehydes ofthe formulae IX and XI react with a hy drazine derivative carrying anacid group, e.g. 4-(4- carboxyphenyl )-semicarbazide, to give thecorresponding hydrazone derivatives, or the alcohols of the formulae lV,Vlll or X react with a dicarboxylic anhydride e.g. phthalic anhydride,to give the racemate of an acid half ester.

These acid racemates can be reacted with optically active bases, e.g.esters of optically active aminoacids, or (-)-brucine, (+)-quinidine,()-quinine, (+)-quinquonine, (+)-dehydroabietylamine, and ephedrine,(+)-and ()-l-phenyl-ethylamine or the N- monoor dialkylated derivativesthereof, to give mixtures consisting of two diastereoisomeric salts,

The racemates cited hereinbefore which contain hydroxy groups can alsobe resolved into their optical antipodes, for which purpose there areused in particular optically active acids, or reactive functionalderivatives thereof, which form diastereoisomeric esters with the citedalcohols. Examples of such acids are: ()-abietic acid, D(+)-andL()-malic acid, N-acylated optically active aminoacids, and ()-camphanicacid, and ()-ketopinic acid, L(+)-ascorbic acid, (+)-camphoric acid,(+)-campher-l0-sulphonic acid([3), (+)or ()-a-bromo-camphor-1r-sulphonicacid, (D(-)-quinic acid, (D()-isoascorbic acid, D()- and L(+)- mandelicacid, (+)-l-methoxyacetic acid, D()- and L(+ )-tartaric acid and thedi-O-benzoyl and di-O-ptoluyl derivatives thereof.

Racemates which contain hydroxy groups can be converted into a mixtureof diastereoisomeric urethanes, for example by reaction with opticallyactive isocyanates, such as (+)-or l phenylethylisocyanate.

It is possible for basic racemates, such as those of the formulae VIIand VIII, to form diastereoisomeric salts with the above cited acids.

Racemates which contain double bonds can be converted, for example withplatinum chloride and l -phenyl-2-aminopropane, into mixtures ofdiastereoisomeric complex salts.

Physicochemical methods are suitable for separating the distereoisomericmixtures, chiefly fractionated crystallisation. But chromatographicmethods can also be used, primarily solid-liquid chromatography.Readily'volatile diastereoisomeric mixtures can be separated also bydistillation or gas chromatography.

The resolution of the separated diastereoisomeric compounds into theoptically active starting materials is also performed by conventionalmethods.

The acids or bases are liberated from the salts, e.g. by treatment withacids or bases which are stronger than those originally used. From theesters and urethanes are obtained the desired optically activecompounds, for example by alkaline hydrolysis or by reduction with acomplex hydride, such as lithium aluminium hydride.

A further method of resolving the racemates consists in chromatographyon optically active absorption layers, for example on cane sugar.

According to a third method, the racemates are dissolved in an opticallyactive solvent and the more sparingly soluble optical antipode iscrystallised out.

In a fourth method, the varying reactivity of the optical antipodes tobiological material, such as microorganisms or isolated enzymes, isutilised.

In a fifth method, the racemates are dissolved and one of the opticalantipodes is crystallised by inoculation with a small amount of anoptically active product obtained by the above methods.

The term lower used to qualify the syllable alk, e.g. in lower alkane,lower alkyl, lower alkoxy, lower alkylene and the like, indicates thatthe respective hydrocarbon radicals contain up to 7 carbon atoms, but ingeneral up to 4 carbon atoms are preferred.

The esters encompassed by the present invention of the formula II, inwhich Z, and/or Z represent esterified hydroxy groups, are derived frominorganic or organic acids. Esters of strong acids are preferred which,accompanied by the splitting off of an acid HZ are able to form thedouble bond required in the next step. Such esters are derived, forexample, from hydrohalic acids such as hydrochloric or hydrobromic acid,but are derived in particular from organic. e.g. aliphatic or aromatic,sulphonic acids, such as lower alkanesulphonic acids which areoptionally substituted by halogen, e.g. methanesulphonic or trifluoroortrichloromethanesulphonic acid, or from benzenesulphonic acids which areoptionally substituted by e.g. one or more lower alkyl, phenyl or nitrogroups or by halogen, e.g. chlorine or bromine, for examplebenzenesulphonic acid, p-toluenesulphonic acid, p-biphenylsulphonicacid, p-nitrobenzenesulphonic acid or p-bromobenzenesulphonic acid.Further esters are those derived from xanthogenic acids, in particularfrom lower alkylxanthogenic acids, eg methylxanthogenie acid, which areable to react in the next step also to form the required double bond.

The present invention also encompasses esters of the formula II whichare derived from weaker or weak inorganic or organic acids. These estersare less suitable for the formation of the required double bond in thenext step; but they can be used, for example, for the purificationand/or characterisation of the diol which falls under the formula II.Such esters are derived, for example, from boric acid, sulphurous acid,phosphorous acid, phosphoric acid, carbonic acid, e.g. from carbonicacid which is monoesterified with tert.-butanol, 2-methyl-butan-2-ol,a,a-dimethyl-p-phenylbenzyl alcohol, a-phcnylbenzyl alcohol,trichloroethanol, 2- iodo-ethanol or benzoylmethanol, also fromaliphatic monocarboxylic acids, for example from lower alkanecarboxylicacids which are optionally substituted by halogen, e.g. acetic acid,propionic acid, butyric acid, or from trifluoroor trichloroacetic acid,from aliphatic dicarboxylic acids, such as oxalic acid or ma- Ionicacid, from aromatic carboxylic acids, such as optionally by one or morealkyl, phenyl or nitro groups or by halogen substituted benzoic acids,e.g. benzoic acid, p-methylbenzoic acid, p-biphenylcarboxylic acid,pnitrobenzoic acid or pmhlorobenzoic acid, or also from aromaticdicarboxylic acids, e.g. optionally substituted benzene dicarboxylicacids, such as phthalic acid.

The compounds of the present invention can be in the form of bothmonoestes and diesters, wherein the ester groups Z, and Z can be eitherthe same or different. Preferred esters are the diesters in which Z, andZ,

are the same.

The compounds of the present invention are manufactured by reducing acompound of the formula I in which X, represents hydrogen and Xrepresents the hydroxy group, or X, and X together represent the 0x0group, and, if desired, esterifying the resulting compound of theformula II, in which Z, and Z each represents a hydroxy group.

As reducing agents there are used preferably complex hydrides, forexample of boron or aluminium, such as alkali metal borohydrides oraluminum hydrides in which 1 to 3 hydrogen atoms are optionally replacedby lower alkoxy or lower alkoxy lower alkyl, e.g. lithium aluminiumhydride, lithium borohydride, sodium borohydride andsodiumbis-(methoxyethoxy)-aluminium hydride, also diborane. The complexhydrides are used advantageously in a solvent which is inert under thereaction conditions. The reduction with lithium alumin ium hydride orlithium borohydride is effected preferably in ethereal liquids, such asin dialkyl ethers, e.g. diethyl ether, in ethylene glycol dialkylethers, e.g. ethylene glycol dimethyl ether, in diethylene glycoldialkyl ethers, e.g. diethylene glycol dimethyl ether, tetrahydrofuranor dioxan. Sodium borohydride can be used advantageously in loweralkanols, such as methanol, ethanol, isopropanol or tert. butanol, inwater or in mixtures thereof. sodium-bis-(methoxyethoxy)- aluminiumhydride is used advantageously in the above mentioned etherealliquidesor in hydrocarbons, such as benzene or toluene.

Depending upon the reagents employed, the process is carried out atreduced or at elevated temperature, preferably about 0 and C.

If in the reduction a start is made from compounds of the formula I, inwhich X, and X together represent the 0x0 group, the reaction proceedsvia the compound of the formula I, in which X, represents hydrogen and Xrepresents the hydroxy group. In certain instances, for example in usingcalculated amounts of the reducing agent, e.g, diisobutylaluminiumhydride, the cited intermediate product can be isolated and finallyfurther reduced up to the final step.

The reaction of the compound of the formula [1, obtained in thereduction, wherein Z, and Z represent hydroxy groups, to the esterswhich also fall under the formula II, is carried out with the acidscited hereinbefore, or, preferably, with their reactive functionalderivatives, advantageously in the presence of acid binding agents.Reactive functional derivatives are primarily simple or mixed anhydridesof the cited acids. Of the mixed anhydrides, the chlorides and bromidesare particularly suitable. As examples there may be cited: aliphatic oraromatic sulphonic acid chlorides, bromides and anhydrides, inparticular methanesulphonic, trifluoromethanesulphonic,benzenesulphonic, p-toluenesulphonic, p-biphenylsulphonic,p-nitrobenzenesulphonic and p-bromobenzesulphonic chloride, and thecorresponding anhydrides and bromides; also acetic, propionic, butyric,trifluoroacetic, benzoic, pchlorobenzoic, p-methylbenzoic,p-phenylbenzoic and p-nitrobenzoic Chloride, and the correspondingbromides and hydrides.

By simple anhydrides are meant those of the respective acids withthemselves, for example acetic anhydride, or also internal anhydrides,for example phthalic anhydride or ketenes.

Suitable for the esterification with hydrohalic acids are in particularthe halides of sulphurous acid, such as thionyl chloride, of phosphorousacid, such as phos phorus trichloride, of phosphoric acid, such asphorphorus pentachloride and phosphoroxy chloride, and of cyanuric acid,such as cyanuric chloride, and the corresponding bromides.

Carbon disulphide, which leads to the derivatives of dithiocarbonicacid, can be used as anhydride of dithiocarbonic acid. The citedxanthogenates can thus be manufactured by treating an alkali metal salt,e.g. the sodium salt of a hydroxy compound falling under the formula II,firstly with carbon disulphide and subsequently with a lower alkylhalide, e.g. methyl iodide.

Further reactive functional derivatives of the cited acids are theiresters, for example of lower alkanols, or in particular their activatedesters, such as the phenyl esters which are optionally substituted byone or more nitro groups, cyanmethyl esters or the esters of N-hydroxy-phthalimide.

As acid binding agents there are used inorganic oases, such as salts ofalkali or alkaline earth metals with weak acids, for example alkali oralkaline earth :arbonates such as sodium, potassium or calciumcaraonate, or the corresponding bicarbonates, or organic oases,preferably tertiary aliphatic or aromatic amines, such as tri-loweralkylamines, e.g. triethylamine, diiso- Jropylethylamine,dicycloalkyl-lower alkylamines, e.g. :licyclohexylamine, and di-loweralkyl anilines, e.g. dimethyl aniline, nitrogen-containing heterocycles,such as pyridine, lower alkylpyridines and N-lower alkyl- Jiperidine ormorpholine, or amides, such as dimethyl :"ormamide or dimethyl acetamideor hexamethylphosahoric acid triamide, or basic ion exchangers. Strongaases are used advantageously in approximately stoi- :hiometric amounts,and weak bases in excess.

As solvents it is possible to use an excess of the liquid acid bindingagents cited hereinbefore. Advantageously, however, the process iscarried out in a diluent which is inert under the reaction conditions,for exam- Jle in the ethereal liquids cited hereinabove, in hydro-:arbons, such as toluene, or benzene, in chlorinated hyirocarbons, suchas methylene chloride or chloroform.

The esterification can be carried out at reduced or elevatedtemperature, preferably between about 30 and 100C.

By using equimolar amounts of the compound of the "ormula ll, wherein Zand Z are hydroxy groups, and )f the reactive acid derivatives, thereare obtained pref- :rably monoesters of the formula II, wherein Zrepreients an esterified hydroxy group and Z represents a "ree hydroxygroup. On the other hand, by using two :quivalents of the reactive acidderivatives, there are )btained diesters of the formula II, in whichboth hy iroxy groups are esterified with the same acid.

Diestcrs of the formula I], in which Z and Z are diferent, are obtainedby converting the hydroxy group Z of a monoester obtained above into anester group which is different from Z,. If Z is an ester group which :anbe saponified more easily than Z for example one )f the carbonic acidester groups cited hereinbefore, it 5 possible to obtain by partialsaponification of Z and naintaining the ester group Z a monoester, inwhich 2., represents the hydroxy group and Z represents an :sterifiedhydroxy group.

The invention also comprises those embodiments of he process in which astart is made from compounds which are obtainable as intermediateproducts at any stage and the missing steps of the process are carriedout with these, or the process is discontinued at any stage; it is alsopossible to use starting materials in the form of derivatives or whichare formed during the reaction.

Preferred starting materials and reaction conditions are those whichlead to the compounds cited at the outset as being especially preferred.

The starting materials of the formula I which are required for themanufacture of the compounds of the present invention are also new andcan be obtained, for example, according to the lst. step of themulti-step process exemplified at the outset.

The following Examples illustrate the invention, without in any waybeing limitative thereof.

EXAMPLE 1 A mixture of 1.056 g (8 mmols) of cis-cyclohexane-1,3,5-triol, 1.072 g l L6 mmols) of glyoxylic monohydrate, 2.0 g 10.5mmols) of p-toluenesulphonic monohydrate, 50 ml of benzene and 10 ml ofwater is boiled under reflux for 16 hours in a Dean-Stark steam trap.After the reaction solution has cooled, it is decanted off from a smallamount of undissolved resin, washed with 20 ml ofa solution which issaturated with sodium chloride and sodium bicarbonate, and with 35 ml ofwater. The combined washings are extracted with methylene chloride andthe methylene chloride layer is combined with the benzene solution,dried over sodium sulphate and concentrated in a water jet vacuum. Theresidue is recrystallised from methylene chloride/ether to give 2,-5,1l-trioxatricyclo[4,3,1,1 undecan-3-one of the formula la which meltsat l40-143C.

EXAMPLE 1a While stirring, 10.56 g (0.08 mols) ofcis-cyc1ohexane-l,3,5-triol and 10.72 g (0.116 mols) of glyoxylicmonohydrate in 400 ml of ethylene glycol dimethyl ether are heated untilall is dissolved. To the cooled solution are added carefully 96 g ofAmberlyst l5 (strongly acid catalyst in pearl form, Rohm and Haas Co.)[dried for 4 hours at C and 0.05 Torr]. The resulting suspension isboiled under reflux for 30 minutes, cooled and filtered. The Amberlyst15 which is filtered off is washed twice with 60 ml of ethylene glycoldimethyl ether each time and then with 1000 ml of methylene chloride.The filtrate is combined with the washings and extracted with 400 ml ofnormal sodium bicarbonate solution. The sodium bicarbonate solution iswashed with 300 ml of methylene chloride, the methylene chloridesolution is combined with the previously obtained organic solutions andthese are dried over sodium sulphate and evaporated in a water jetvacuum. The crystalline residue is recrystallised from methylenechloride/ether to give 2,5,1 l-trioxatricyclo[4,3,l,l "lundecan-3-one ofthe formula la (m.p. -l43C).

EXAMPLE lb A mixture of 500 mg (0.378 mmols) ofcis-cyclohexane-1,3,5-triol and 920 mg (0.567 mmols) of methyldiethoxyacetate in 20 ml of ethylene glycol dimethyl ether is heatedunder reflux, treated after 15 minutes with 2 g of predried Amberlyst 15(see Example la) and boiled for a further 10 hours under reflux withstirring. The catalyst is filtered off hot and washed twice with 20 mlof methylene chloride. The filtrate is concentrated under reducedpressure, the residue is taken up in the combined methylene chloridefractions and the resulting solution is shaken with l ml of water. Theisolated aqueous layer is extracted with l0 ml of methylene chloride andthe combined methylene chloride fractions are dried with anhydroussodium sulphate and the solvent is distilled off. The crystallineresidue is treated with 2 ml of ether and the crystalline 2,-5,1ltrioxatricyclo[4,3,1,11 undecan-3-one of the formula la is collectedby suction filtration (m.p. l40-l43C).

EXAMPLE 2 a. Analogous to Example l, the 2,5,l l-trioxatricyclo[4,3,l,l' ]undecan-3-ol of the formula lb H OH is obtained from theglyoxal hydrate and cis-cyclohexane-l,3,5-triol. Melting point:l85-l94C.

b. To a stirred solution of 340 mg of 3,5,11- trioxatricyclo[4,3,l,llundecan-3-one are added dropwise within 10 minutes under nitrogen andat room temperature, 2.8 ml of a 20% solution of diisobutylaluminiumhydride in toluene. After a further 30 minutes at room temperature thereaction mixture is shaken with 0.8 ml of water and 2 g of silica gelfor l5 minutes and, upon addition of 8 g of sodium sulphate, filteredthrough a glass filter. The filter cake is extracted with a small amountof methylene chloride. The solvent is distilled off from the combinedfiltrates under reduced pressure to give pure 2,5,1 1-trioxatricyclo[4,3,l ,l "]undecan-3-ol of the formula lb, which melts atl85l94C (sublimation at 145C).

c. A solution of 340 mg of 2,5,1 l-trioxatricyclo[4,3,l l'lundecan-3-one in 10 ml of absolute ethanol is treated with 300 mg ofsodium. After the metal has dissolved the reaction mixture is treatedwith l0 ml of water and 0.7 ml of acetic acid, concentrated underreduced pressure to about 3 ml and the concentrate is extracted withmethylene chloride. The solvent is evaporated to leave as residue pure2,5,1 l-trioxatricyclo- [4,3,1,l lundecan-Ii-ol,

EXAMPLE 3 A solution of 8.50 g (0.05 mols) of 2,5,lltrioxatricyclo[4,3,l ,l""]undecan-3-one of the formula la in 90 ml ofethylene glycol dimethyl ether is added dropwise within minutes, whilestirring and cooling with ice, to a suspension of 2.0g (0.05 mols) oflithium aluminium hydride in 60 ml of ethylene glycol dimethyl ether.The reaction mixture is boiled for 15 minutes under reflux, cooled toroom temperature and carefully treated with l0 ml of ethyl acetate todestroy excess lithium aluminium hydride. Then, while stirring, 2.0 mlof water, 2.0 ml of 15% sodium hydroxide solution, and

H HO-CHZ f t- OH (Ila) EXAMPLE 3a A solution of 340 mg of 2,5,1l-trioxatricy clo[4,3,l,l""] undecan-3-one of the formula la in 10 ml ofabsolute ethanol is treated at room temperature with mg of sodiumborohydried and the mixture is stirred for 2 hours. The reaction mixtureis diluted with l0 ml of water, the pH adjusted to 8 with a few drops ofglacial acetic acid and the resulting solution is concentrated underreduced pressure to about 3 ml. The concentrate is extracted 3 timeswith altogether lOO ml of methylene chloride, the combined extracts aredried with sodium sulphate and the solvent is distilled off to give3-hydroxymethyl-2,4-dioxabicyclo[ 3,3,1 ]nonan- 7-01 of the formula Ila,which melts at l46l49C.

EXAMPLE 3b A similar 3 hour reduction of 340 mg of 2,5,lltrioxatricyclo[4,3,l,l Iundecan-3-one of the formula la in 10 ml ofisopropanol with 150 mg of sodium borohydried at 50C, and subsequentworking up as described hereinabove, leads to the same compound of theformula Ila.

EXAMPLE 3c To a solution of 340 mg (Zmmols) of 2,5,1 1-trioxatricyclol4,3,l ,l lundecan-3-one in l0 ml of methanol are addedall at once 150 mg of sodium borohydride while stirring and cooling tol2l5C(water bath). After 1 1 /2 hours, during which time the bathtemperature is allowed to rise to 20C, a further 150 mg of sodiumborohydride are added and the mixture is stirred for 2 /2 hours at 20C.The reaction mixture is then treated with 10 ml of water, the pHadjusted to 8 with a few drops of acetic acid, and concentrated underreduced pressure to about 3 ml. The concentrate is extracted three timeswith 25 ml of methylene chloride on each occasion, the combined extractsare dried over sodium sulphate and the solvent is distilled off (at theconclusion under reduced pressure) to give crystalline3-hydroxymethyl-2,4-dioxabicyclo [3,3,l lnonan-7-ol of the formula Ila(m.p.l46-l49 C).

EXAMPLE 4 A solution of 0.87 g (5 mmols) of 3-hydroxymethyl-2,4-dioxabicyclol 3,3,l ]nonan-7-ol of the formula Ila in 5 ml ofanhydrous pyridine is cooled to 20C and, while stirring, treated withl,l ml (14,2 mmols) of methanesulphonyl chloride. The cooling bath isremoved and the reaction mixture is added after 1% hours to 40 ml of anormal sodium bicarbonate solution. The re sulting mixture is extractedsuccessively with 40 ml of ethyl acetate and 40 ml of methylenechloride. The

combined organic solutions are washed with 10 ml of sodium bicarbonatesolution, dried over magnesium sulphate and concentrated in a water jetvacuum. The crude product is recrystallised from acetonc/hcptanc andgives 7-methylsulphonyloxy-3- methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1 ]nonane of the formula llb L CH SO O-CH To 080 011 m.p. l37l38C.

EXAMPLE 5 To a solution of 348 mg (2 mmols) of 3-hydroxymethyl-2,4-dioxabicyclo[3,3,llnonanJ-ol of the formula Ila in 2.0ml of absolute pyridine are added at -l5C with stirring [.28 g ofp-bromobenzenesulphochloride all at once and the resulting mixture isfurther stirred under nitrogen for 48 hours at room temperature. Thereaction mixture is treated with 25 ml of methylene chloride and shakensuccessively with ml of 8% NaHCO and l5 ml of sodium chloride solution.The aqueous layers are extracted once more with methylene chloride. Thecombined organic phases are dried over sodium sulphate and freed fromsolvent and pyridine in a water jet vacuum and finally in an oil pump,to leave as residue crude 7-(pbromophenylsulphonyloxy)-3-pbromophenylsulphonyloxymethy] )-2,4-dioxabicyclo [3,3,l ]nonane of the formula llc Br- Q -so 0- cs whichcongeals to a crystalline solid on standing. It is crystallised fromboiling benzene with the addition of a small amount of hexane. Meltingpoint: l28C; the crystals contain mols of benzene.

EXAMPLE 6 A solution of 1.65 g (5 mmols) of 7-methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4- dioxabicyclol3,3,l]nonane of the formula [lb and 3.0 ml mmols) ofl,5-diazabicyclo[5,4,0]undec-5-ene in ml of anhydrous dimethylsulphoxide is heated for 45 minutes to 1 10C. The reaction mixture iscooled to room temperature and then diluted with 150 ml of ether. It isthen washed successively with 75 ml of Zn hydrochloric acid, 100 ml ofwater and finally with 100 ml of normal sodium bicarbonate solution. Theaqueous layers are extracted separately twice with ISO ml of ether oneach occasion. The last ethereal extract is washed with 50 ml of waterand each organic extract is finally washed with 50 ml of concentratedsodium chloride solution. The organic solutions are dried over magnesiumsulphate and evaporated in a water jet vacuum.

Chromatography of the residue on basic aluminium oxide (activity levelIV) with benzene as eluant results in a racemic mixture of3-methylsulphonyloxymethyl- 2,4-dioxabicyclo[3,3,1]non-6-ene of theformula llla H CH SCLO-CH +0- 3 a 2 O and its optical antipode, with amelting point of S4-59C.

EXAMPLE 6a A solution of 660 mg of 7-methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3,3,! ]nonane of the formulalib and 1.4 g of tetrabutylammonium fluoride in 7.5 ml of dimethylformamide is heated under nitrogen for 7 hours to 60C. The cooledreaction mixture is treated with 20 ml of methylene chloride and ml ofether and shaken successively with 80 ml of an 8% sodium bicarbonatesolution, I00 ml of water and 50 ml of sodium chloride solution. Theaqueous layers are extracted separately twice with ml of the samesolvent mixture on each occasion. The combined organic fractions aredried over sodium sulphate. The solvent is distilled off under reducedpressure to give an oily product whose spectrum properties correspond tothose of the pure racemic 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1

non-6-ene of the formula llla. Preparative chromatography on basicaluminium oxide with benzene as eluant gives the crystalline product ofmelting point 535 6C.

EXAMPLE 6 b A mixture of 300 mg (0.9l mmols) of 7- methylsulphonyloxy.3-methylsulphonyloxymethyl-2,4- dioxabicyclo[3,3,l ]nonane of theformula lib and 15 ml of anhydrous toluene is heated to 80C and treatedwithin 2 hours in S amounts of altogether 300 mg of potassiumtert.butylate dissolved in 5 ml of tert. butanol. The reaction mixtureis stirred for a further 2 hours, then cooled, treated with saturatedsodium chloride solution and extracted 5 times with l0 ml of methylenechloride on each occasion. The combined organic extracts are washed oncemore with saturated sodium chioride solution, dried over magnesiumsulphate and concentrated. Preparative chromatography of the resultingresidue on silica gel with ethyl acetate as eluant yields a racemicmixture consisting of 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1 non-6-ene of the formula llla and its optical antipode of meltingpoint 5058C.

EXAMPLE 6c A solution of 60mg (0.18 mmoles) of 7-methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,l]nonane of the formula llb in 3 ml of ethylene glycoldimethyl ether (filtered through basic aluminium oxide) is heated to 80Cand treated with a solution of 60 mg (0.54 mmols) of sublimed potassiumtert. butylate in 0.7 ml of tert. butanol. The reaction mixture iscooled after 4 hours, treated with a saturated sodium chloride solutionand extracted 5 times with 6 ml of methylene chloride on each occa sion.The organic phases are dried over magnesium sulphate, and the solvent isevaporated. Preparative layer chromatography on silica gel with ethylacetate as eluant yields a racemic mixture consisting of 3-methylsulphonyloxymethyl-2,4-dioxabicyclol3,3,1]- non-6-ene and itsoptical antipode.

EXAMPLE 6d A solution of 80 mg (0.24 mmoles)methylsulphonyloxy-3-methylsulphonyloxy methyl- 2,4-dioxabicyclo[3,3,llnonane of the formula Ilb in 2 ml of dimethyl sulphoxide (which hasbeen dried over calcium hydride) is treated dropwise within 10 minuteswith a solution of 100 mg of potassium tert. butylate (0.89 mmols) in 3ml of dimethyl sulphoxide. The reaction temperature is kept at l5C. Thereaction mixture is then diluted with 10 ml of ether and washed with 8ml of 0.5 n hydrochloric acid and 10 ml of saturated sodium bicarbonatesolution. The aqueous layers are extracted twice with l ml of ether oneach occasion. The combined organic phases are washed again with ml ofsodium bicarbonate solution and ml of water, dried over magnesiumsulphate and concentrated in vacuo to give a racemic mixture consistingof 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3,3, l non-6-ene offormula Illa and its optical antipode.

EXAMPLE 6e A solution of 100 mg (0.3 mmols) of 7-methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4- dioxabicyclol 3.3,l]nonane of the formula Ilb in 5ml of tert. butanol (distilled overcalcium hydride) is heated to 80C and 60 mg (0.54 mmols) of sublimedpotassium tert. butylate dissolved in 2 ml of tert. butanol are addedwithin 1 hour. The reaction mixture is heated for 6 hours at the sametemperature, and then a further ll.0 mg. (0.1 mmols) of potassium tert.butylate, dissolved in 0.5 ml of tert. butanol, are added. The reactionmixture is heated for a further hour, cooled, treated with 40 ml ofether and washed 5 times with ml of water each time. The organic phaseis dried over magnesium sulphate and evaporated to give a racemicmixture consisting of 3-methylsulphonyloxymethyl-2,4- dioxabicyclo[3,3,llnon-6-ene of the formula Illa and its optical antipodes, in the form ofa colourless oil which crystallises on standing and is sufficiently purefor use in the following reaction.

EXAMPLE 6f 7-methylsulphonyl0xy-3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,l lnonane (280 mg) is added to 5 ml of a boiling 2npotassium hydroxide solution in ab solute alcohol and the mixture isboiled for 2 minutes under reflux while stirring vigorously. Thereaction mixture which has congealed to a crystalline solid is cooledand, after treatment with 5 ml of 8% sodium bicarbonate solution,extracted three times with methylene chloride. The combined extracts aredried with sodium sulphate and the solvent is distilled off underreduced pressure to leave as residue the crystalline racemic3-methylsulphonyloxymethyl-2,4-dioxabicy clo[3,3,l lnon o-ene (m.p.5356).

EXAMPLE 6g To a hot suspension of 280 mg of 7-methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]nonane in 2,5 ml of isopropanol is added 2.5 ml ofaboiling 2 n potassium hydroxide solution in isopropanol while stirringvigorously, and the resulting reaction mixture is boiled under refluxfor 3 minutes. The reaction mixture is cooled and treated with 5 ml ofan 8% sodium bicarbonate solution, then extracted 3 times with methylenechloride. The combined extracts are dried over sodium sulphate and thesolvent is distilled off in vacuo under reduced pressure to leave asresidue the racemic 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3,3,1non-6-ene in the form of a colourless oil, which soon congeals to acrystalline solid (mp. 5356C).

EXAMPLE 7 A solution of 61bromophenylsulphonyloxy)3-(pbromophenylsulphonyloxymethyl)-2,4-dioxabicyclo[3,3,l]nonaneof the formula lIc and 220 mg of tetra-n-butylammonium fluoride in l .0ml of anhydrous dimethyl formamide is heated with stirring in a nitrogenatmosphere for 45 minutes to 60C. The cooled reaction mixture is treatedwith 5 ml of methylene chloride and 25 ml of ether and shakensuccessively with 8 ml of normal sodium bicarbonate solution. 10 ml ofwater and 10 ml of sodium chloride solution. The aqueous phases areextracted twice with 10 ml of the same solvent mixture on each occasion.All organic phases are dried together over sodium sulphate. The solventis distilled off under reduced pressure to yield a racemic mg of7-(pmixture consisting of 3-(pbromophenylsulphonyloxymethyl)-2,4-dioxabicyc]o[3,3,l lnon-6-ene of the formula lIlb (IIIb) and itsoptical antipode; m.p. ll4-1 l7C.

EXAMPLE 8 A solution of 363 mg (1.55 mmols) of racemic 3-methylsulphonyloxymethyl-2,4 dioxabicyclo[3,3, l non6-ene and 215 mgl.55 mmols) of potassium carbonate in 3.6 ml of acetone and 18 ml ofwater is stirred in a nitrogen atmosphere for 18 hours under reflux. Thecooled reaction mixture is extracted 3 times with 30 ml of methylenechloride on each occasion.

The combined methylene chloride layers are concentrated, the residue istaken up in ethyl acetate and filtered through a column of l0 g of basicaluminium oxide (activity level IV). Elution is performed with ethylacetate. Concentration of the first 60 ml of eluate in a water jetvacuum yields a racemic mixture of 9,10-dioxatricyclo[4,3,l,0"-"ldecan4fi-ol of the formula IVa o (Iva) and itsoptical antipode, which melts after recrystallisation at 134-l42C(210232C, sealed capillary).

EXAMPLE 8a A solution of 75 mg (0.32 mmols) of racemic 3-methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3,3,1 non-6-ene of theformula Illa and 44 mg (0.32 mmols) of potassium carbonate in 0.5 ml ofethylene glycol dimethyl ether and 2.5 ml of water, is stirred for 18hours under reflux in an oil bath which is kept at 100C. The cooledreaction solution is diluted with water, saturated with NaCl andextracted times with ml of methylene chloride on each occasion. Thecombined extracts are dried over magnesium sulphate and concentrated.The residue is resolved by means of preparative layer chromatography (onsilica gel, eluant: methylene chloride/acetone 1:1 A racemic mixture of9,10- dioxatricyclo[4,3,l ,0 "]decan-4/3-ol of the formula [Va and itsoptical antipode is obtained.

EXAMPLE 8b To a well stirred suspension of 16.5 g (0.05 mols) of racemic7-methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]nonane in 125 ml ofboiling isopropanol is added a hot solution of 14 g of potassiumhydroxide (0.25 mol) in 125 ml of isopropanol in one amount. In a fewseconds a clear solution temporarily forms from which, however,potassium mesylate soon begins to precipitate. After stirring vigorouslyfor 3 minutes at the boiling temperature of the solvent, the reactionmixture which in the meantime has congealed to a crystalline solid istreated with a solution of 25 g of potassium bicarbonate in 1250 ml ofwater and about 250 ml are distilled off under reduced pressure from theresulting clear solution. The reaction mixture is then brought to theoriginal volume by adding water and boiled under reflux for 16 hours ina nitrogen atmosphere. It is then cooled, saturated with sodium chlorideand repeatedly extracted with methylene chloride. The combined extractsare dried over sodium sulphate and the solvent is distilled off underreduced pressure to give the crystalline racemic mixture of9,10-dioxatricyclo(4,3,l,0'"ldecan-4,B-o1 and its optical antipode. Insimilar manner it is also possible to use a 2n solution of potassiumhydroxide in ethanol or in water/ethylene glycol monomethyl ether (2:1)for the splitting off of the methanesulphonic acid. The product can befurther used without purification or purified as follows via itsacetate:

A solution of 1.46 g of the racemic 9,10-dioxatricyclo[4,3,l,0"]decan-4[3-ol in 25 ml of pyridine and 8 ml of acetic anhydride isallowed to stand for 14 hours at room temperature and then evaporated ina high vacuum. The residue is recrystallised from diethyl ether to givethe pure racemic 4B-acetoxy-9,10-di0xatricy clo[4,3,l,0"' ]decane whichmelts at 9798C.

A solution of 198 mg of the pure racemic 4B-acetoxy-9,l0-dioxatricyclo[4,3,1,0 "]decane in 8 ml of ethanol and 2 mlof 2n aqueous potassium hydroxide is boiled under reflux for 1 hour in anitrogen atmosphere. The ethanol is then distilled off in vacuo and theresidue is extracted 4 times with 20 ml of methylene chloride on eachoccasion. The methylene chloride so lutions are evaporated and the pure9,10-dioxatricyclo[4,3,1,0 ldecan-4fi-ol is obtained, which afterrecrystallisation from benzene/cyclohexane melts at 250256C (sealedcapillary).

EXAMPLE 8c A solution of 1.56 g 10.0 mmols) of the pure racemic9,10-dioxatricyclo[4,3,l,0 *]decan-4B-ol (purifled via the acetate) in15 ml of pyridine is treated, while stirring, with 2.50 g (l2.5mmols) of(S)- ketopinylchloride (prepared from S-ketopininc acid with thionylchloride/pyridine. S-ketopinic acid is prepared from(+)-lO-camphorsulphonic acid monohydrate analogous to the processdescribed in Organic Syntheses 45, 14,55). The reaction mixture isstirred for 18 hours at room temperature and added to a mix ture of 25ml of saturated sodium carbonate solution and 25 ml of water. Themixture is extracted 3 times with 50 ml of methylene chloride on eachoccasion. The methylene chloride solution is treated with ben zene, thenevaporated in vacuo, and the residue recrystallised 4 times from ethylacetate to give the pure 8S-4B-(S-ketopinyloxy)-9,10-dioxatricyclo[4,3,l ,0 "]decane, [0],, 47 (c=lin chloroform) which melts at l83l85C. The mother liquor contains thecrude 8R- 4,8-(S-ketopinyloxy)-9, l 0-dioxatricyclo[4,3, l ,0 decanewhich melts at l l l-l 14C. A solution of 1.28 g (4.0 mmols) of the pure8S-4/3-(Sketopinyloxy)- 9,l0-dioxatricyclol4,3,l,0 ]decane and 8.0 ml ofZn aqueous potassium hydroxide in 32 ml of ethanol is boiled underreflux for 15 hours in a nitrogen atmosphere. The solution is thencooled, the ethanol evaporated in vacuo, the residue treated with 5 mlof water and extracted 6 times with 50 m1 of methylene chloride on eachoccasion. The combined methylene chloride layers are evaporated, and theresidue is first sublimed at 1 10C (0.02 Torr) and then recrystallisedfrom benzene/cyclohexane. The pure 88-9, 10- dioxatricyclo{4,3,l,0]decan-4B-ol of the formula lVa melts at 251-256C, [01] l47 (c l in chloroform).

EXAMPLE 8d A solution of 1.56 g 10.0 mmols) of the racemic 9,1-0-dioxatricyclo[4,3, l ,0 ]decan-4,B-ol (purified via the acetate) in 30ml of dry benzene is boiled for 14 hours under reflux with 1 ml oftriethylamine and 2.2 g (15 mmols) of ()-1phenyl-ethylisocyanate. Afterevaporation in vacuo and drying in a high vacuum at 50C the residue iscrystallised out from ethyl acetate/hexane and recrystallised 5 timesfrom benzene. The resulting pure urethane melts at l44145C and has thefollowing optical rotation: [01]!) 32 (c=1 in chloroform). This urethane(50 mg) is boiled under reflux with 1.0 ml of 2n potassium hydroxidesolution in ethanol. The mixture is then treated with water 10 ml) andconcen trated to 5 ml. The solution is washed 3 times with 20 ml ofpentane on each occasion, then concentrated to 1 ml and the concentrateis extracted 5 times with 20 ml of methylene chloride on each occasion.The combined methylene chloride solutions are filtered through cottonwool and evaporated. The residue, 8S-9,10-dioxatricyclo[4,3,l,0'"]decan-4Bol, has the optical rotation 1] -l47(c=l in chloroform).

In analogous manner it is possible to obtain the 8R-9,l-dioxatricyclo[4,3,l ,0 l-decan-4l3-ol with the optical rotation[01],, +l47 (c=l in chloroform) from the pure racemic9.lOdioxatricyclo[4,3,l,0 ldecan- 4B-ol with the aid of(+)-lphenyl-ethylisocyanate.

EXAMPLE 8e A solution of I00 mg of the racemic 4B,5B-epoxy-9,]0-dioxatricyclo[4,3,l ,0 '"]decane in 3 ml of dry tetrahydrofuran isboiled under reflux for 14 hours with 200 mg of lithium aluminiumhydride. The mixture is then cooled, 0.2 ml of water, 0.2 ml of Znsodium hydroxide solution and 0.6 ml of water are added and theresulting suspension is stirred for 1 hour at room temperature. It isthen filtered with suction and the precipitate is washed 3 times with ISml of methylene chloride on each occasion. The organic solutions areevaporated to yield the pure racemic 9,l0-dioxatricyclo 4,3 ,1 ,0]decan-4B-ol.

EXAMPLE 9 While stirring, a solution of 0.24 ml of methanesulphonylchloride in 5.0 ml of methylene chloride is added at a temperature ofl0C to a solution of 156 mg (1.00 mmols) of racemio9,l0-dioxatricyclo[4,3.l,O ldecan-4fl-ol and 0.55 ml (4.00 mmols) oftriethylamine in 5.0 ml of methylene chloride. After 40 minutes. duringwhich time the cooling bath has warmed to 0C, the reaction mixture isdiluted with 25 ml of methylene chloride and washed with ml of normalsodium bicarbonate solution. The sodium bicarbonate layer is washed with10 ml of methylene chloride and this methylene chloride layer iscombined with the previous methylene chloride solution, dried oversodium sulphate and concentrated in a water jet vacuum. The residue istaken up in a small amount of ethyl acetate and filtered through acolumn of 5 g of basic aluminium oxide (activity level IV). Afterelution with ethyl acetate and concentrating the first 50 ml of theeluate there is obtained as residue a crude racemic mixture of4Bmethylsulphonyloxy-9,lO-dioxatricyclol4,3,l ,0 ldecane of the formulalVb CH S020 (IVb) and its optical antipode, which can be used in thenext reaction without further purification. However, it can also berecrystallised from ethyl acetate/pentane or ether/methylene chloride.Melting point: lO2-106C. ln analogous manner the8S-4/3-methylsulphonyloxy- 9,l0-dioxatricyclo[4,3,l.0']decane of theformula IVb, which melts at 120C (with decomp.) ethyl acetate/hexanfl,la] =90 (c=l in chloroform), is obtained from the85-9.l0-dioxatricyclo[4,3. l .O ldeCan-4B-QI.

EXAMPLE 9a A solution of 550 mg (3.52 mmols) of the racemic9,l0dioxatricyclol4,3,l,0 "]decan-4B-ol in 25 ml of ether (filtered overbasic aluminium oxide) is treated with 900 mg of sodium hydride (50%)and the mixture is boiled under reflux for 3 hours. Then 2 ml of carbondisulphide are added and heating is continued for 3 hours. Finally, 2 mlof methyl iodide are added and the mixture is refluxed for a further 4hours. The reaction mixture is cooled and excess sodium hydride is thendestroyed with moist ether and subsequently with water. The organicphase is isolated and dried over magnesium sulphate. The solvent isexpelled and the resulting oil is dissolved in benzene and filtered overaluminium oxide (activity level IV). After an extremely unpleasantsmelling component has passed out of the column the eluate is combinedand evaporated. Repeated crystallisation of the residue from heptaneyields the racemic mixture consisting of 9, l0-dioxatricyclo[4,3,l,0decane-4B-methylxanthogenate of the formula lVc ll ocsca (IVc) and itsoptical antipode; m.p. 8l82C.

EXAMPLE l0 A solution of the crude racemic 4B- methylsulphonyloxy-Q,l0-dioxatricyclo[4.3, l ,0 ""]decane of the formula IVb, obtained inExample 9, in 1.0 ml of anhydrous dimethyl sulphoxide, is treated in anitrogen atmosphere and with stirring with 2.5ml of a freshly preparednormal solution of potassium tert. butylate in anhydrous dimethylsulphoxide, and the mixture is stirred for 40 minutes. The reactionsolution is then diluted with 50 ml of ether and washed 4 times with 10ml of water on each occasion and once with 20 ml of saturated sodiumchloride solution. The organic layer is concentrated, the residue takenup in a small amount of methylene chloride and the solution is filteredthrough a column of 2 g of basic aluminium oxide (activity level IV).After elution with methylene chloride and concentrating the first 50 mlof eluate in a water jet vacuum there is obtained as residue the racemicmixture of 9,l0-dioxatricyclo[4,3,l,0 ]dec-4-ene of the formula V andits optical antipode, in the form of a wax-like substance; m.p.l03-l05C. From 8S-4B methylsulphonyloxy-Q, l0-dioxatricyclol4,3.l,0""]decane there is obtained in analogous manner -9,]0-

dioxatricyclo[4.3.l,0"]dec-4-ene, m.p. l08l 14C, [01],, +1 l (c=l inchloroform).

EXAMPLE 1021 To a boiling solution of 4.68 g of racemic 4B-methylsulphonyloxy-9, l 0-dioxatricyclo[ 4,3, l ,O ]decane in 40 ml ofisopropanol is added a hot solution of 4.48 g of potassium hydroxide inthe same solvent in a single amount and the resulting reaction mixtureis'refluxed for 2 hours with stirring. During this time the reactionmixture congeals to a crystalline solid from the precipitated potassiummesylate. It is then treated with I ml of 8% sodium bicarbonate solutionand repeatedly extracted with methylene chloride. The combined extractsare dried over sodium sulphate and evaporated under reduced pressure.The resulting crude product is dissolved in pentane/ether (9:1 andfiltered through a column filled with 100 g of aluminium oxide (activitylevel IV). The first 500 ml of eluate yield after evaporation theracemic mixture of 9,lO-dioxatricyclo[4,3,l ,0"""ldec-4-ene of theformula V, and its optical antipode.

EXAMPLE 10b To a solution of racemic 9,10- dioxatricyclol 4,3 ,l,0]decane-4B-methylxanthogenate in methylene chloride is added the tenfold amount of sodium carbonate and the solvent is distilled off in arotary evaporator. The resulting composition is heated to 150C in apyrolysis tube. The distillate which is collected contains the racemic9,10-dioxatricyclo[ 4,3,l ,0']dec-4-ene.

EXAMPLE 1 l To a solution of 165 mg of racemic9,l0-dioxatricyclo[4,3,1,0 ']dec-4-ene in 4 ml of methanol are added,with stirring and at room temperature 865 mg of potassium bicarbonateand 740 mg of benzonitrile. To this mixture are added at intervals of 8hours 5 portions each of 0.3 ml of 30% hydrogen peroxide and stirring iscontinued for hours. Methylene chloride (25 ml) is then added to thereaction mixture, which is washed with 2% sodium hydrogen carbonatesolution, dried over sodium sulphate and concentrated. Benzamide whichhas formed is removed by crystallisation from methylenechloride/pentane. The residual oil can be used directly in the nextreaction, or chromatographed on 22 g of basic aluminium oxide (activitylevel IV). Elution with petroleum ether/benzene (7:3) yields the racemicmixture of 45,5B-epoxy-9,lO-dioxatricyclo[4,3,l,0" ]decane of theformula and its antipode, (m.p. after crystallisation from ether/-pentane: l8l-l82C), and also as main product the racemic mixture of4oz,5a-epoxy-9,lO-dioxatricyclo[4,3,l ,O Idecane of the formula and itsantipode; (m.p. after crystallisation from ether/- pentane: l46l56C).

From 88-9, 1 0-dioxatricyclol 4,3, l ,0"]dec-4-ene there is obtained inanalogous manner the 8S-4a,5aepoxy-9, lO-dioxatricyclo[4,3, l ,0']decaneMelting point: l69l7 1 [01 ],;=95 (c l in chloroform) and the 8S-4B,5B-epoxy-9, l 0- dioxatricyclo[4,3,l,0) decane Melting point:l-l82,[al,,=87 (c l in chloroform) EXAMPLE 1 la To a solution of 350 mg(2,53 mmols) of racemic 9,- 10-dioxatricyc1o[4,3,l,0 ]dec-4-ene in 45 mlof chloroform (filtered through aluminium oxide of activity level I) areadded l.] g l l mmols) of finely powdered potassium bicarbonate andthen, with stirring, 570 mg of m-chloroperbenzoic acid (2.8 mmols). Themixture is stirred for 40 hours at room temperature, filtered and thefiltrate is washed twice with 30 ml of a normal sodium carbonatesolution on each occasion. The organic solution is filtered throughcotton wool and evaporated. The residue is chromatographed on 20 g ofbasic aluminium oxide (activity level IV). The racemic 413,5B-epoxy-9, l0-dioxatricyclo[4,3,l ,0 ]decane is eluted as main product withpetroleum ether/- benzene(7:3)and the racemic4a,5a-9,l0-dioxatricyclo[4,3,l ,0'"]decane with benzene.

EXAMPLE 12 and its optical antipode, in the form of colourless crystals(m.p. l78180C-, sublimation at about 140C).

In analogous manner there is obtained from the8S-4a,5a-epoxy-9-,l0-dioxatricyclo[4 ,3 ,l ,0 ]decane the8S-4B-amino-9,l0-dioxatricyclo[4,3,l,0"]decan- 5a-ol; m.p. 176l78,[a]p=l55 (c=1 chloroform).

EXAMPLE 12a A solution of M3 mg of the crude mixture of racemic4a,5o:-epoxy-9, l 0-dioxatricyclo[4,3. l ,o ldecane and thecorresponding fi-epoxide in 5 ml of 24% aqueous ammonia is heated in aCarius tube under nitrogen for l hour to C (bath temperature). Uponcooling, the contents of the tube are evaporated to dryness in vacuo,the residue is dissolved in 5 ml of water, and this solution is washedtwice with lOml of diethyl ether on each occasion to remove unreactedB-epoxide. The aqueous phase is concentrated to yield the pure racemic4B-amino-9,l0-dioxatricyclo[4,3,l,0 l-decan5a- 01 (mp. l78l80C).

EXAMPLE 13 The racemic 4B-amino-9 lO-dioxatricyclo[4,3,1,0"]decan-5oz-ol (400 mg, 2.34 mmols) is dissolvedin 18 ml of a 1.23% solution of hydrochloric acid in methanol and thesolution is stirred under nitrogen for 2 hours at room temperature.During this time the racemic 2-exo-amino-3,4-endo-dihydroxy8-methoxy-7-oxabicyclo{4,3,0lnonane hydrochloride begins to crystallisefrom the reaction solution. The resulting suspension is evaporated todryness in vacuo and the white crystalline residue is freed from excesshydrogen chloride by addition of a few ml of methanol and distilling itoff. The resulting 2-exo-amino-3,4- endo-dihydroxy-8-methoxy-7-oxabicyclo[4,3,0]nonane hydrochloride racemate, consisting of thecompound of the formula 901-1 Q i a 5 "H2 l'lCl (VIII 2.)

EXAMPLE 14 A solution of 45.6 mg of racemic 9,10-dioxatricyclo [4.3,l,O""]dec-4-ene and mg of p-toluenesulphonie acid in 1.0 ml of methanol isstirred for 45 minutes at room temperature, treated with 3 ml of sodiumbicarbonate solution (8%) and extracted 3 times with ethyl acetate. Thecombined extracts are dried over sodium sulphate and evaporated invacuo. The oily residue is the racemic 4-endo-hydroxy8-methoxy-7oxabicyclo[4,3,0]non-2-enc (thin layer chromatography on silica gel withethyl acetate as eluant, Rf: 0.36) consisting of the compound of theformula OCH and its optical antipode.

EXAMPLE 15 A solution of 51 mg of the racemic 4-endo-hydroxy-8-methoxy-7-oxabicyclo[4,3,0]non-2-ene in 3ml of methylene chloride isstirred at room temperature for 26% hours in the presence of an excessof potassium bicarbonate. Then 5 ml of methylene chloride are added, themixture is extracted with 3 ml of 2% sodium bicarbonate solution, andthe methylene chloride phase is dried over sodium sulphate andevaporated in vacuo. The residue is chromatographed on 7 g of aluminiumoxide (activity level IV), in the course of which the racemic mixtureconsisting of2,3-exo-epoxy-4-endohydroxy-S-methoxy-7-oxabicyclo[4,3.0]nonane of theformula and its optical antipode is eluted with methylene chloride.Elution with ethyl acetate/methanol (9:1) yields the racemic mixtureconsisting of 2,3-endo-epoxy-4- endo-hydroxy-8-methoxy-7-oxabicyclo[4,3,01nonane of the formula (VI'a) and its optical antipode.

EXAMPLE 15a A mixture of 51 mg of the racemic 4-endo-hydroxy-8-meth0xy-7-oxabicyclo[4,3,01non-2-ene, 1 ml of methanol, 183 mg ofbcnzonitrile, 217 mg of potassium bicarbonate and 34mg of hydrogenperoxide is stirred at room temperature and treated after 17 and 26hours respectively with 34 mg of 90% hydrogen peroxide on each occasion.After a further 16 hours 3 ml of water and 10 ml of methylene chlorideare added. The organic phase is isolated, extracted 3 times with 10%sodium bicarbonate solution, the aqueous extracts are reextracted 3times with methylene chloride and the combined organic phases are driedover sodium sulphate and evaporated. The benzamide is removed from theresulting reaction product by crystallisation from methylenechloride/pentane and the residue is chromatograhed on 7 g of aluminiumoxide (activity level IV). Elution with methylene chloride/ethyl acetate(:1 yields the racemic mixture consisting of 2,3-exo-epoxy-4-endo-hydroxy-8-methoxy-7-oxabicyclo [4,3,0]nonane and itsoptical antipode. Further elution with ethyl acetate/methanol (9:1)yields the racemic mixture consisting of 2,3-endo-epoxy-4-endo-hydroxy-8-methoxy-7-oxabicyclo[4,3,0}nonane and its optical antipode.

EXAMPLE b A solution of 64 mg of the racemic 4-endo-acetoxy-8-methoxy-7-oxabicyclo[4,3,0]non2ene, 207 mg of N-bromacetamide in 15 mlof acetone and 6 ml of water is stirred for 16 hours at room temperatureand the acetone is subsequently removed in vacuo. The aqueous solutionis extracted with altogether 19 ml of methylene chloride and themethylene chloride extracts are washed with 2 ml of 2% sodiumthiosulphate solution. dried over sodium sulphate and evaporated.Preparative thin layer chromatography of the residue on silica gel(methylene chloride/ethyl acetate 4:1) yields a mixture of isomericbromohydrins. This mixture is stirred for 1 hour in 2 ml of 2.5%potassium hydroxide in methanol and to the mixture are added ml of waterand sodium chloride until saturation is reached. The saturated solutionis then extracted 4 times with 15 ml of methylene chloride on eachoccasion. The methylene chloride solution is dried over sodium sulphateand then evaporated. The residue is resolved analogous to Example 15ainto the racemic 2,3- endo-epoxy-4-endo-hydroxy-8-methoxy-7-oxabicyclo[4.3.0]nonane and the corresponding 2,3-exo-epoxy racemate.

The starting material is obtained in the following manner:

A solution of 170 mg of the racemic 4-endo-hydroxy-8-methoxy-7-oxabicyclo[4.3,0]non 2ene in 1.5 ml of acetic anhydride and5 ml of pyridine is stirred for 5 hours at room temperature. Volatilecomponents are distilled off in a high vacuum, again at roomtemperature, and the residue is treated with toluene and distillationperformed once more. The oily residue is chromatographed on preparativesilica gel plates with ethyl acetate. The racemic4-endo-acetoxy-8-methoxy-7- oxabicyclo[4,3,0]non-2-ene is obtained as anoily product.

EXAMPLE 150 A solution of 62mg racemic 4a,5a-epoxy-9,10- dioxatricyclo[4,3,l,0 ]decane in 6 ml of dry methanol is treated at 0C with 6 mg ofp-toluenesulphonic acid and stirred at the same temperature for 1 hour.Then 50mg offine by pulverised potassium bicarbonate are added and themixture is stirred for 5 minutes, filtered and evaporated. The residueconsists ofa racemic mixture of 2,3-endo-cpoxy-4-endo-hydroxy-8-methoxy-7-oxabicyclo [4,3,0]nonane of the formula Vl'a and its opticalantipode.

EXAMPLE 16 A solution of 30 mg of the racemic 2,3-endo-epoxy4-endo-hydroxy-8-methoxy-7- 0xabicyclol4,3,0]nonane in 0.3 ml of dioxanand 2 ml of 24% aqueous ammonia is heated in a sealed test tube for 1hour to 120C. The product is evaporated in vacuo, whereupon the racemicmixture consisting of 2-exo-amino-3,4-endo-dihydroxy-8-methoxy-7-oxabicyclo [4,3,0]nonane of the formula V111, and its optical antipode,is obtained as a colourless oil.

EXAMPLE 1? The racemic 2-exo-amino-3,4-endo-dihydroxy-8-methoxy-7-oxabicyclo[4,3,0lnonane hydrochloride(350 mg; 1.46 mmols) and250 mg (1.84 mmols) of crystalline sodium acetate are dissolved at 05Cin 6 ml of 50% aqueous acetic acid. While stirring and cooling with anice-water bath, 1.5 ml of a 3 normal sodium nitrite solution are addedto the resulting solution in an argon atmosphere within 40 minutes.After a total of minutes, the reaction mixture is neutralised with asuspension of 6 g of sodium hydrogen carbonate in 12 ml of water andextracted repeatedly with methylene chloride. The combined extracts aredried with sodium sulphate and the solvent is then dis tilled off invacuo. The oily residue is the racemic 6- exo-formyl-3-methoxy-2-oxabicyclo[3.3,0] octan-7- endo-ol, consisting of thecompound of the formula CHO and its optical antipode. Thin layerchromatogram: R, 0.28 on silica gel with ethyl acetate as eluant.

From the 6S-2-exo-amino-3,4-endo-dihydroxy-8-methoxy-7oxabicyclo[4,3,01nonane hydrochloride there is obtained inanalogous manner thelS-6-exoformyl-3-methoxy-2-oxabicyclo[3,3,0]octan-7-endo- 01.

The product is instable and is used at once.

EXAMPLE 17a A solution of 25 mg (0.123 mmols) of the racemic2-exo-amino-3,4-cndo-dihydroxy-8-methoxy-7- oxabicyclo[4,3,0] nonane in5 ml ofdry ethylene glycol dimethyl ether is treated at 0C with mg ofpotassium acetate while stirring, and dinitrogen tetroxide is passedinto the solution slowly over the course of 10 minutes. Excessdinitrogen tetroxide is then removed by scavenging with nitrogen, thesolution is treated with 10 ml of water and 1 ml of saturated sodiumcarbonate solution and extracted with methylene chloride. The organicextract is dried over sodium sulphate and then evaporated. The residueis the racemic 6-exo-formyl-3- methoxy-2-oxabicyclo[3,3,0]oetan-7-endo-ol, which consists of the compound of the formulaIXa and its optical antipode.

EXAMPLE 18 A solution of 29.6 mg (0.158 mmols) of freshly manufacturedracemic 6-exo-formyl-3-methoxy-2- oxabicyclo[3,3,0] octan-7-endo-ol in 3ml of dry ethylene glycol dimethyl ether is treated with 120 mg (0.32mmols) of l-triphenylphosphoranylidene-2-heptanone. (S. M. Miyano et al,Tetr. Letters 1969 1615 and J. Org. Chem. 37. 1810). The resultingsolution is refluxed under nitrogen for l l hours, cooled andconcentrated. The residue is purified by preparative thinlayerchromatography on silica gel with ethyl acetate as eluant.

The resulting racemic 3-methoxy-6-exo-(3-oxotrans-1-octenyl)-2-oxabicyclo [3 ,3,0]octan-7-endo-ol which consists of thecompound of the formula and its optical antipode is a yellow oil, whichin the infrared zone has absorption maxima at 2.80; 2.90; 5.92; 5.98;6.1541. and in the ultraviolet zone at 230m The melting point of its7end0-(3,5-dinitrobenzoyloxy) derivative (obtained from the aboveproduct with 3.5- dinitrobenzoyl chloride and pyridine) is 7375,5C.

EXAMPLE 18a A solution of 550 mg (2.96 mmols) of the freshlymanufactured racemic o-exo-formyb3-methoxy-2- oxabicyclo[3,3,0]octan-7-endo-ol in 18 ml of dry ethylene glycol dimethyl ether istreated with 1.39 g (4.4 mmols) ofl-tributylphosphoranyIidene-Z-heptanone (b.p. 130C at 0.001 Torr, (S. N.Finch and J. J. Fitt, Tetr. Letters 1969 4639). The resulting solutionis stirred under nitrogen for 2 hours at 50C and for 12 hours at roomtemperature, then concentrated in vacuo. The residue, the racemic3-methoxy-6-exo-(3- oxo-transl-octenyl )-2-oxabicyclo[ 3,3,0] octan-7-endo-ol is purified by preparative thin layer chromatography on silicagel with ethyl acetate as eluant. (Oil, which congrats to a crystallinesolid on standing at 20, m.p. 8.59.5C).

In analogous manner there is obtained from the lS-6-exo-3-methoxy-2-oxabicyclo[3.3,0]octan-7-endo-ol the lS-3methoxy-6-exo(3-oxo-transl -octenyl )-2- oxabicyclol3,3,01octan-7-endo-ol; m.p.ll.513C [a],,' 69il (c l 7: in chloroform).

EXAMPLE l9 A solution of 50 mg (0.177 mmols) of the racemic3-methoxy-6-exo-( 3-oxo-transl -octenyl )-2- xabicyclo[3,3,0]octan-7-endo-ol in 9 ml of methanol is treated at 0C while stirring witha solution of 338 mg (8.95 mmols) of sodium borohydride in 3 ml ofwater. The solution is stirred for 17 minutes at 0C, then poured on 150ml ofwater, The resulting solution is extracted 3 times with 50 ml ofchloroform on each occasion, the combined extracts are dried overmagnesium sulphate, evaporated, and the residue is dried for 1 hour invacuo at 25C and 0.1 Torr. The residual oil is separated into twofractions by preparative thin layer chromatography on silica gel withethyl acetate as eluant. The less polar fraction consists of the racemic3- methoxy-6-exo-( 3R-hydroxy-transl -octenyl )-2-oxabicyclo[3,3,0loctan-7-endo-ol, consisting of the compound of theformula 9 @VYW (X) 5H H0 ii and its optical antipode (R on silica gelwith ethyl acetate as eluant 0.3 1; mp. of its bis-p-nitrobenzoyloxyderivative, obtained from the above product with pnitrobenzoyl chlorideand pyridine, is 7276C); and the more polar one consists of the racemic3-methoxy- 6-exo-( 3S-hydroxy-transl -octenyl )-2- oxabicyclol3,3,0loctan-7-endo-ol which consists of the compound of the formula OCHand its optical antipode (R; on silica gel with ethyl acetate as eluant0,25; m.p. of its bis p-nitrobenzoyloxy derivative is l35l37.5).

From the lS-3-methoxy-6-exo-( 3-oxo-trans-loctenyl)-2-oxabicyclo[3,3,01octan-7-endo-ol there is obtained inanalogous manner the lS-3'methoxy-6- exo-(BS-hydroxy-trans-l-octenyl)-2-oxabicyclo[3,3,01octan-7-endo-ol;oil [a],, "=72il (C =20] inchloroform), and the lS-3-methoxy-6-exo- (3R-hydroxy-transl -octenyl)-2-oxabicyclo[ 3,3 ,0 ]octan-7-endo-ol, m.p. 5057C, [a],, =88:1 (c l inchloroform).

The 3-methoxy-6-exo-( 3R-hydroxy-transl -octenyl)- 2-oxabicyclo[3,3,0loctan-7-endo-ol which occurs as by-product can be led back intothe process as follows:

A solution of 50 mg of the racemic 3-methoxy-6-exo- (3R-hydroxy-transl-octcnyl )-2oxabicyclo[ 3,3 ,0]octan-7-endo-ol in 0.78 ml of methylenechloride is stirred in a nitrogen atmosphere for 17 hours with 782 mg ofactive precipitated manganese dioxide (Merck, Darmstadt). The mixture isthen filtered through diato maceous earth and evaporated. The residue isthe racemic 3-methoxy-6-cxo-( 3oxo-transl -octenyl )-2oxabicyclo[3,3,0]octan7-endo-ol.

1 claim:

1. 3-hydroXymethyl-2,4-dioxabicyclol3,3,l lnonan- 7-0].

2. A compound of formula II herein Z and Z are the same. and eachrepresents a iydroxy group which is esterified with an aliphatic orromatic sulphonic acid.

3. A compound of formula [I a n 1% L 17- 2 in) wherein Z and Z are thesame and each represents a iydroxy group which is esterified with alower alkaneulphonic acid, or a halo-substituted lower alkane sulhonicacid.

4. 7-methylsulphonyloxy-3- methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1 ]noname, according to claim 3.

5. A compound of formula II clo[ 3,3 lnonane, according to claim 5.

1. 3-HYDROXYMETHYL-2,4-DIOXABICYCLO(3,3,1)NONAN-7-OL.
 2. A compound offormula II
 3. A compound of formula II 4.7-methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4-dioxabicyclo(3,3,1)nonane, according to claim
 3. 5. A compound offormula II 6.7-(p-bromophenylsulphonyloxy)-3-(p-bromophenylsulphonyloxymethyl)-2,4-dioxabicyclo(3,3,1)nonane, according to claim 5.